title: Design, synthesis and structure-activity relationship of functionalized tetrahydro-β-carboline derivatives as novel PDE5 inhibitors.
abstract: Starting from tadalafil as a template, a series of functionalized tetrahydro-β-carboline derivatives have been prepared and identified as novel potent and selective PDE5 inhibitors. Replacing the 3,4-methylenedioxyphenyl at position 6 of tadalafil, together with elongation of the N2-methyl substituent and manipulation of the stereochemical aspects of the two chiral carbons led to the identification of compound XXI, a highly potent PDE5 inhibitor (IC(50)  = 3 nM). Compound XXI was also highly selective for PDE5 versus PDE3B, PDE4B, and PDE11A, with a selectivity index of 52 and 235 towards PDE5 rather than PDE11 with both cAMP and cGMP as substrate, respectively.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt. nermin.salah@guc.edu.eg
authors.forename: Nermin S
authors.initials: NS
authors.lastname: Ahmed
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Gary
authors.forename: Hethar N
authors.initials: HN
authors.lastname: Tinsley
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
authors.forename: Ashraf H
authors.initials: AH
authors.lastname: Abadi
mesh_terms: D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D058986:Phosphodiesterase 5 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000068581:Tadalafil
chemical_list: D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; C009804:tryptoline; D000068581:Tadalafil; D000242:Cyclic AMP; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP